The simian type D retroviruses are the cause of Simian Acquired Immunodeficiency Syndrome in biomedical research communities in Asian macaques, and can serve as model systems in understanding the role of envelope (env) glycoprotein gene diversity in modulating cell tropism and onset in AIDS pathogenesis. Retroviruses undergo high-frequency mutations in their env genes and are subjected to selection pressures that result in the appearance of new pathologically-advantaged variants. We have molecularly-cloned and sequenced the complete genomes of a type D simian retrovirus (SRV serogroup 2; D2/RHE/OR) and variant viruses recovered from rhesus macaques endemically infected with the prototypical serogroup 2 virus. Infectious molecular genomes of D2/RHE/OR and one variant, D2/RHE/OR/V1, have been recovered. Reciprocal chimeric viruses were constructed to analyze the contributions made by viral genomic determinants to in vitro infectivity of lymphoid cells. These exp eriments indicate that D2/RHE/OR has a reduced ability to infect T-cell lines, especially Hut-78 and MT-cells, and that multiple viral genomic determinants influence tropism. In addition, we have isolated infectious molecular clones of serogroup 4 (D4/CYN/CA) and serogroup 5 (D5/RHE/OR) SRVs. Complete sequence analyses of these additional genomic clones indicate that serogroups 4 and 5 SRVs are genetically-distinct from all previously characterized serogroups. In recent work, with the use of the yeast two hybrid system, we are now attempting to molecularly-clone the genes encoding env-interactive proteins, including potential SRV receptor and cell signaling molecules. The complete sequence analyses of the serogroup 2, 4 and 5 SRVs has provided important information concerning the genetic diversity of the simian retroviruses. These molecular clones and the potential identification of the SRV receptor and cell signaling molecules will provide the necessary molecular reagents for future struc ture-function and cell/tissue tropism experiments. FUNDING RR00163/AIDS Supplement Project 8 PUBLICATIONS Moudgil T, Machida CA. Yeast two-hybrid system identification of molecules interacting with simian retroviral env gene products. In Program of the Sixteen Annual Symposium on Nonhuman Primate Models for AIDS (held in Atlanta, GA, October 7-10, 1998) (abstract 78).